Mortality from cirrhosis: lack of progress over the last 35 years.
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England↗
Biomedical subjects
C Gluud
Publications and source records attributed to C Gluud.
Dopaminergic agonists for hepatic encephalopathy.
BACKGROUND: Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of dopaminergic agonists for patients with hepatic encephalopathy. SEARCH STRATEGY: Trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register (July 2004), The Cochrane Central Register of Controlled Trials (Issue 3, 2004), MEDLINE (1966-2004/07), EMBASE (1980-2004/07), manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: All randomised trials comparing dopaminergic agonists versus placebo or no intervention for hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: Trial inclusion and data extraction were made independently by two reviewers. Binary outcomes are reported as odds ratios (OR) with 95% confidence intervals (CI) based on a random effects model. The presence of statistical heterogeneity was explored by the chi-squared test with significance set at P < 0.1. Potential sources of heterogeneity were explored through subgroup analyses with regard to the type of hepatic encephalopathy and type of dopaminergic agonist. MAIN RESULTS: Five trials were included. Four trials had low methodological quality. Compared with placebo or no treatment, dopaminergic agonists had no significant effect on the risk of no improvement (OR 0.33, 95% CI 0.01 to 11.25, two trials, 80 patients) or mortality (OR 1.11, 95% CI 0.34 to 3.54, four trials, 139 patients). There was significant heterogeneity (P = 0.09) among trial results on the risk of no improvement, but not on mortality (P = 0.19). The treatment response was not significantly different with regard to the type of hepatic encephalopathy or dopaminergic agonist, but the analyses had very low power to detect potential differences. There was a nonsignificant trend that dopaminergic agonists may be associated with adverse events (OR 8.33, 95% CI 0.37 to 187.74, 2 trials, 13 patients). All adverse events (n = 7) occurred in the experimental group. REVIEWERS' CONCLUSIONS: This review does not provide evidence that dopaminergic agonists are of benefit to patients with acute or chronic hepatic encephalopathy, or fulminant hepatic failure. The review is limited by the small number of trials performed within this field, the low number of patients randomised in each trial, and the low methodological quality of included trials. Accordingly, there is also insufficient evidence to exclude a potential beneficial effect. Dopaminergic agonists should not be used for hepatic encephalopathy, but may be assessed in future randomised clinical trials.
Dopamine Agonists↗
Antioxidant supplements for preventing gastrointestinal cancers.
BACKGROUND: Oxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory. OBJECTIVES: To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers. SEARCH STRATEGY: We identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 1, 2003), MEDLINE, EMBASE, LILACS, and SCI-EXPANDED from inception to February 2003, and The Chinese Biomedical Database (March 2003). We scanned reference lists and contacted pharmaceutical companies. SELECTION CRITERIA: Randomised trials comparing antioxidant supplements to placebo/no intervention examining the incidence of gastrointestinal cancers. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted data. The outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse events. Outcomes were reported as relative risks (RR) with 95% confidence interval (CI) based on fixed and random effects meta-analyses. MAIN RESULTS: We identified 14 randomised trials (170,525 participants), assessing beta-carotene (9 trials), vitamin A (4 trials), vitamin C (4 trials), vitamin E (5 trials), and selenium (6 trials). Trial quality was generally high. Heterogeneity was low to moderate. Neither the fixed effect (RR 0.96, 95% CI 0.88 to 1.04) nor random effects meta-analyses (RR 0.90, 95% CI 0.77 to 1.05) showed significant effects of supplementation with antioxidants on the incidences of gastrointestinal cancers. Among the seven high-quality trials reporting on mortality (131,727 participants), the fixed effect (RR 1.06, 95% CI 1.02 to 1.10) unlike the random effects meta-analysis (RR 1.06, 95% CI 0.98 to 1.15) showed that antioxidant supplements significantly increased mortality. Two low-quality trials (32,302 participants) found no significant effect of antioxidant supplementation on mortality. The difference between the mortality estimates in high- and low-quality trials was significant by test of interaction (z = 2.10, P = 0.04). Beta-carotene and vitamin A (RR 1.29, 95% CI 1.14 to 1.45) and beta-carotene and vitamin E (RR 1.10, 95% CI 1.01 to 1.20) significantly increased mortality, while beta-carotene alone only tended to do so (RR 1.05, 95% CI 0.99 to 1.11). Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In four trials (three with unclear/inadequate methodology), selenium showed significant beneficial effect on gastrointestinal cancer incidences. REVIEWERS' CONCLUSIONS: We could not find evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, they seem to increase overall mortality. The potential cancer preventive effect of selenium should be studied in adequately conducted randomised trials.
Antioxidants↗
D-penicillamine for primary biliary cirrhosis.
BACKGROUND: D-penicillamine is used for patients with primary biliary cirrhosis due to its hepatic copper decreasing and immunomodulatory potentials. The results from randomised clinical trials have been inconsistent. OBJECTIVES: To systematically review the beneficial and harmful effects of D-penicillamine for patients with primary biliary cirrhosis. SEARCH STRATEGY: We identified trials through electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register (September 2003), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 3, 2003), MEDLINE (January 1966 to September 2003), EMBASE (January 1980 to September 2003), The Chinese Biomedical CD Database (January 1979 to August 2003), and LILACS (1982 to 2003); through manual searches of bibliographies; and by contacting authors of the trials and pharmaceutical companies. SELECTION CRITERIA: We included randomised clinical trials comparing D-penicillamine with placebo/no intervention or other control intervention irrespective of language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the methodological quality of the trials and extracted data, validated by a third reviewer. The primary outcomes were 1) mortality and 2) a combination of those who died or underwent liver transplantation. We analysed dichotomous outcomes as relative risk (RR) with 95% confidence interval (CI) by a fixed effect model and a random effects model. We investigated sources of heterogeneity by subgroup analyses and tested the robustness of our findings by sensitivity analyses. MAIN RESULTS: We included seven trials randomising 706 patients with primary biliary cirrhosis. D-penicillamine compared with placebo/no intervention tended to increase mortality (RR 1.34, 95% CI 1.09 to 1.64, fixed; RR 1.46, 95% CI 0.85 to 2.50, random). However, there was substantial heterogeneity. No significant differences were detected regarding the risks of mortality or liver transplantation, pruritus, liver complications, progression of liver histological stage, or the levels of liver biochemical variables (except alanine aminotransferase). D-penicillamine versus placebo/no intervention significantly increased the risk of adverse events (RR 3.11, 95% CI 2.33 to 4.16, fixed; RR 4.18, 95% CI 1.38 to 12.69, random). REVIEWERS' CONCLUSIONS: D-penicillamine did not appear to reduce the risk of mortality, but significantly increased the occurrences of adverse events in patients with primary biliary cirrhosis. We do not support the use of D-penicillamine for patients with primary biliary cirrhosis.
Chelating Agents↗
Benzodiazepine receptor antagonists for hepatic encephalopathy.
BACKGROUND: Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of benzodiazepine receptor antagonists for patients with hepatic encephalopathy. SEARCH STRATEGY: Eligible trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library, MEDLINE and EMBASE (last search: January 2004), reference lists of relevant articles, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: Randomised trials comparing any benzodiazepine receptor antagonist versus placebo or no intervention for hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: Two reviewers independently included trials and extracted data. Binary outcomes are reported as risk difference (RD) with 95% confidence intervals (CI) based on a random effects model. Statistical heterogeneity was explored by a chi-squared test with significance set at P < 0.1. The inconsistency across trials was assessed by I(2). Potential sources of heterogeneity were explored through subgroup analyses. MAIN RESULTS: Thirteen randomised trials with 805 patients were included. Eight trials used a crossover design. All trials were double-blind and assessed flumazenil versus placebo. Data on all outcomes could not be extracted from all trials. The included patients had a favourable prognosis (361/390 [93%] survived in the flumazenil group versus 345/376 [92%] in the placebo group). Flumazenil had a significant beneficial effect on improvement of hepatic encephalopathy at the end of treatment (RD 0.28; 95% CI 0.20 to 0.37, eight trials). Flumazenil had no significant effect on recovery (RD 0.13; 95% CI -0.09 to 0.36, two trials) or mortality RD 0.01; 95% CI -0.05 to 0.07, 10 trials). Flumazenil may be associated with adverse events, but trial results were heterogeneous. REVIEWERS' CONCLUSIONS: Flumazenil had a significant beneficial effect on short-term improvement of hepatic encephalopathy in patients with cirrhosis and a highly favourable prognosis. Flumazenil had no significant effect on recovery or survival. Considering the fluctuating nature of hepatic encephalopathy, future trials should use a parallel design and assess if treatment with flumazenil leads to a sustained improvement or increased recovery and survival. Until this has been demonstrated, flumazenil may be considered for patients with chronic liver disease and hepatic encephalopathy, but cannot be recommended for routine clinical use.
Acute Disease↗
Glucocorticosteroids for viral hepatitis C.
BACKGROUND: Hepatitis C virus may cause liver inflammation and fibrosis. It is not known whether glucocorticosteroids are beneficial or harmful for patients with hepatitis C infection. OBJECTIVES: The objectives were to evaluate the beneficial and harmful effects of glucocorticosteroids for patients with acute or chronic hepatitis C infection with or without hepatitis C related autoimmune disorders. SEARCH STRATEGY: Searches of The Cochrane Hepato-Biliary Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of relevant articles and hand searches of relevant journals were performed in July 2003. Principal authors of clinical trials were approached. SELECTION CRITERIA: Randomised clinical trials dealing with glucocorticosteroids for viral hepatitis C - acute or chronic with or without autoimmune disorders. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer and validated by another. Further information was sought by correspondence with the principal investigator of the trial in case the relevant data were not published. Disagreements were solved by discussion before the meta-analysis. MAIN RESULTS: Eight trials randomised 384 patients with chronic hepatitis C to glucocorticosteroids plus interferon versus interferon plus placebo/no intervention, glucocorticosteroids versus interferon, or glucocorticosteroids versus placebo. Glucocorticosteroids treatment given as short pre-treatment followed by interferon or as long-term parallel treatment combined with interferon versus interferon monotherapy had no significant effect on mortality (no deaths occurred; 342 patients), virological response at six months follow-up (RR 0.85; 95% CI 0.52 to 1.38; 38 patients), or biochemical response at six months follow-up (RR 0.95; 95% CI 0.84 to 1.06; 307 patients). There was no significant difference in serious adverse events between combination therapy versus interferon monotherapy (RR 4.76; 95% CI 0.24 to 93.19; 342 patients). Glucocorticosteroids versus interferon had no significant effect on mortality (RR 2.33; 95% CI 0.27 to 17.80; 13 patients) or virological response at follow-up (RR 1.17; 95% CI 0.86 to 1.58; 13 patients). We found no trials on glucocorticosteroids for acute hepatitis C. REVIEWERS' CONCLUSIONS: There is insufficient evidence neither to confirm nor exclude both beneficial and harmful effects of glucocorticosteroids for chronic hepatitis C with or without autoimmune disorders. This Review is not able to rule out potential serious adverse effects of glucocorticosteroids. Therefore, this Review cannot establish whether glucocorticosteroids treatment can be safely administrated for indications requiring glucocorticosteroids without analysing for hepatitis C virus. The effect of glucocorticosteroids for acute hepatitis C has not been examined in randomised trials.
Acute Disease↗
Nonabsorbable disaccharides for hepatic encephalopathy.
BACKGROUND: Nonabsorbable disaccharides (lactulose or lactitol) are considered the treatment of choice for hepatic encephalopathy. OBJECTIVES: To assess the beneficial and harmful effects of nonabsorbable disaccharides for patients with hepatic encephalopathy. SEARCH STRATEGY: Trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register (March 2003), The Cochrane Central Register of Controlled Trials (Issue 1, 2003), MEDLINE (1966 to 2003/03), EMBASE (1980 to 2003/03), manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: Randomised trials comparing lactulose or lactitol versus no intervention, placebo, or antibiotics and trials comparing lactulose versus lactitol for hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: The primary outcome measures included no improvement of hepatic encephalopathy and all-cause mortality. Binary outcomes are reported as relative risks (RR) based on a random effects model. Subgroup analyses were performed with regard to methodological quality and form of hepatic encephalopathy. MAIN RESULTS: Thirty trials assessed nonabsorbable disaccharides versus placebo, no intervention, or antibiotics or assessed lactulose versus lactitol. We could not extract data from all trials. Compared with placebo or no intervention, nonabsorbable disaccharides had no statistically significant effect on mortality (RR 0.41, 95% CI 0.02 to 8.68, four trials), but appeared to reduce the risk of no improvement of hepatic encephalopathy (RR 0.62, 95% CI 0.46 to 0.84, six trials). However, this result may reflect bias due to low methodological quality of the majority of included trials. Trials of high methodological quality found no significant effect of nonabsorbable disaccharides on the risk of no improvement (RR 0.92, 95% CI 0.42 to 2.04, two trials). We found no statistically significant difference between lactulose and lactitol on mortality (two trials) or risk of no improvement (four trials). However, our meta-analyses were underpowered to establish whether these treatments have comparable effect. Nonabsorbable disaccharides appeared to be inferior to antibiotics on reducing the risk of no improvement (RR 1.24, 95% CI 1.02 to 1.50, 10 trials). REVIEWERS' CONCLUSIONS: This systematic review questions the beneficial effects of nonabsorbable disaccharides and highlights that there is insufficient high-quality evidence to support this treatment. We found that antibiotics appeared to be superior to nonabsorbable disaccharides in improving hepatic encephalopathy, but it is unclear whether this difference in treatment effect is clinically important to patients. Nonabsorbable disaccharides should not serve as comparator in randomised trials on hepatic encephalopathy.
Anti-Bacterial Agents↗
Artificial and bioartificial support systems for liver failure.
BACKGROUND: Artificial and bioartificial liver support systems may 'bridge' patients with acute or acute-on-chronic liver failure to liver transplantation or recovery. OBJECTIVES: To evaluate beneficial and harmful effects of artificial and bioartificial support systems for acute and acute-on-chronic liver failure. SEARCH STRATEGY: Trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register (September 2002), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 3, 2002), MEDLINE (1966 - September 2002), EMBASE (1985 - September 2002), and The Chinese Biomedical Database (September 2002), manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials on artificial or bioartificial support systems for acute or acute on-chronic liver failure were included irrespective of blinding, publication status, or language. Non-randomised studies were included in explorative analyses. DATA COLLECTION AND ANALYSIS: Data were extracted independently by three reviewers. Results were presented as relative risks (RR) with 95% confidence intervals (CI). Sources of heterogeneity were explored through sensitivity analyses and meta-regression. The primary outcome was mortality. MAIN RESULTS: Twelve trials on artificial or bioartificial support systems versus standard medical therapy (483 patients) and two trials comparing different artificial support systems (105 patients) were included. Most trials had unclear methodological quality. Compared to standard medical therapy, support systems had no significant effect on mortality (RR 0.86; 95% CI 0.65-1.12) or bridging to liver transplantation (RR 0.87; 95% CI 0.73-1.05), but a significant beneficial effect on hepatic encephalopathy (RR 0.67; 95% CI 0.52-0.86). Meta-regression indicated that the effect of support systems depended on the type of liver failure (P = 0.03). In subgroup analyses, artificial support systems appeared to reduce mortality by 33% in acute-on-chronic liver failure (RR 0.67; 95% CI 0.51-0.90), but not in acute liver failure (RR 0.95; 95% CI 0.71-1.29). Two trials comparing artificial support systems showed significant mortality reductions with intermittent versus continuous haemofiltration (RR 0.58; 95% CI 0.36-0.94) and no significant difference between five versus ten hours of charcoal haemoperfusion (RR 1.03; 95% CI 0.65-1.62). The incidence of adverse events was inconsistently reported. REVIEWER'S CONCLUSIONS: This Review indicates that artificial support systems may reduce mortality in acute-on-chronic liver failure. Artificial and bioartificial support systems did not appear to affect mortality in acute liver failure. However, considering the strength of the evidence additional randomised clinical trials are needed before any support system can be recommended for routine use.
Chronic Disease↗
Glucocorticosteroids for primary sclerosing cholangitis.
BACKGROUND: Glucocorticosteroids have been suggested for primary sclerosing cholangitis, which is characterised by chronic inflammation and fibrosis in the intrahepatic and extrahepatic biliary tree. OBJECTIVES: To assess the beneficial and harmful effects of glucocorticosteroids for patients with primary sclerosing cholangitis. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials on The Cochrane Library, MEDLINE, EMBASE from their inception until March 2003, and reference lists. SELECTION CRITERIA: Randomised clinical trials comparing any dose or duration of glucocorticosteroids versus placebo, no intervention, or other immunosuppressive agents. We included trials irrespective of language, blinding, or publication status. DATA COLLECTION AND ANALYSIS: Both reviewers extracted data independently and assessed the methodological quality by the generation of the allocation sequence, allocation concealment, double blinding, and follow-up. The results of the meta-analyses were presented as relative risks or weighted mean difference (WMD), both with 95% confidence intervals (CI). The primary outcome measures were mortality and liver-related morbidity. MAIN RESULTS: Two randomised clinical trials were eligible for inclusion. One trial compared biliary lavage with hydrocortisone versus saline in 17 patients. A significant number of adverse events (pancreatitis; cholangitis with septicaemia; paranoid ideas; fluid retention) and no cholangiographic improvement led to termination of the trial. The other trial compared budesonide versus prednisone in 18 patients. Patients had significantly higher serum bilirubin concentration after treatment with prednisone compared with budesonide (WMD 10.4 micro mol/litre, 95% CI 1.16 to 19.64 micro mol/litre). No other significant effects on clinical or biochemical outcomes were identified for any of the evaluated interventions. REVIEWERS' CONCLUSIONS: There is no evidence to support or refute peroral glucocorticosteroids for patients with primary sclerosing cholangitis.
Anti-Inflammatory Agents↗
Colchicine for primary biliary cirrhosis.
BACKGROUND: Colchicine has been used for patients with primary biliary cirrhosis because of its immunomodulatory and antifibrotic potential. The therapeutical responses to colchicine in randomised clinical trials were inconsistent. OBJECTIVES: To evaluate the beneficial and harmful effects of colchicine in patients with primary biliary cirrhosis. SEARCH STRATEGY: We identified trials through electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials on The Cochrane Library, MEDLINE, EMBASE (September 2003), and manual searches of bibliographies. We contacted authors of trials and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials comparing colchicine with any kind of control therapy were included irrespective of language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS: The primary outcomes were the number of deaths and the number of death and/or patients who underwent liver transplantation. Dichotomous outcomes were reported as relative risk (RR) with 95% confidence interval (CI). We examined intervention effects by using both a fixed effect model and a random effects model. Heterogeneity was investigated by subgroup analyses and sensitivity analyses. MAIN RESULTS: Eleven randomised clinical trials involving 716 patients with primary biliary cirrhosis fulfilled the inclusion criteria. No significant differences were detected between colchicine and placebo/no intervention on the number of deaths (RR 1.21, 95% CI 0.71 to 2.06), the number of deaths and/or patients who underwent liver transplantation (RR 1.00, 95% CI 0.67 to 1.49), liver complications, liver biochemical variables, liver histological measurements, and adverse events. Trial methodology was generally low and some trials had high drop-out rate. A best-worst-case-scenario analysis showed no significant effect of colchicine on mortality (RR 0.59, 95%CI 0.30 to 1.15), while a worst-best-case-scenario analysis showed a significant detrimental effect of colchicine on mortality (RR 2.28, 95% CI 1.17 to 4.44). Colchicine significantly decreased the number of patients without improvement of pruritus (RR 0.75, 95% CI 0.65 to 0.87). However, this estimate was based on only 156 patients from three trials. The effect of the combined treatment with ursodeoxycholic acid was not significantly different from that of colchicine alone. REVIEWERS' CONCLUSIONS: We did not find evidence either to support or refute the use of colchicine for patients with primary biliary cirrhosis. As we are not able to exclude a detrimental effect of colchicine, we suggest that it is only used in randomised clinical trials.
Cholagogues and Choleretics↗
Branched-chain amino acids for hepatic encephalopathy.
BACKGROUND: Hepatic encephalopathy may be caused by a decreased plasma ratio of branched-chain amino acids (BCAA) to aromatic amino acids. Treatment with BCAA may therefore have a beneficial effect on patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of BCAA for patients with hepatic encephalopathy. SEARCH STRATEGY: We identified trials through The Cochrane Hepato-Biliary Group Controlled Trials Register (September 2002), (Issue 3, 2002), MEDLINE (1966-2002/09) and EMBASE (1980-2002/05), manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: Randomised trials comparing BCAA with any kind of control therapy for hepatic encephalopathy were included, regardless of blinding, language, or publication status. DATA COLLECTION AND ANALYSIS: Trial inclusion and data extraction were made independently by two reviewers. Our primary outcome was improvement of hepatic encephalopathy. Statistical heterogeneity was tested using random effects and fixed effect models. Binary outcomes are reported as risk ratios (RR) based on a random effects model. MAIN RESULTS: Eleven randomised trials (556 patients) assessing BCAA versus carbohydrates, neomycin/lactulose, or isonitrogenous control were included. The median number of patients in each trial was 55 (range 22 to 75). Follow-up after treatment was reported in four trials (median 17 days (range 6 to 30 days)). Compared to the control regimens, BCAA significantly increased the number of patients improving from hepatic encephalopathy at the end of treatment (risk ratio (RR) 1.31, 95% confidence interval (CI) 1.04 to 1.66, nine trials). We found no evidence of an effect of BCAA on survival (RR 1.06, 95% CI 0.98 to 1.14, eight trials) or adverse events (RR 0.97, 95% CI 0.41 to 2.31, three trials). Sensitivity analyses indicated that methodological quality had significant impact on the results. We found no evidence of an effect of BCAA on improvement of hepatic encephalopathy in trials with adequate generation of the allocation sequence (RR 1.01, 95% CI 0.84 to 1.23, three trials), adequate allocation concealment (RR 1.09, 95% CI 0.89 to 1.33, five trials), or adequate double-blinding (RR 1.20, 95% CI 0.83 to 1.73, three trials). REVIEWER'S CONCLUSIONS: We did not find convincing evidence that BCAA had a significant beneficial effect on patients with hepatic encephalopathy. The trials performed in this field were small with short follow-up and most had low methodological quality.
Amino Acids, Branched-Chain↗
Anabolic-androgenic steroids for alcoholic liver disease.
BACKGROUND: Alcohol is one of the most common causes of liver disease in the Western World today. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease. OBJECTIVES: The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for patients with alcoholic liver disease based on the results of randomised clinical trials. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library, MEDLINE, EMBASE, and full text searches were combined (all searched December 2001). Manufacturers and researchers in the field were also contacted. SELECTION CRITERIA: Only randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included. Interventions encompassed anabolic-androgenic steroids at any dose or duration versus placebo or no intervention. The trials could be double blind, single blind, or unblinded. The trials could be unpublished or published and no language limitations were applied. DATA COLLECTION AND ANALYSIS: All analyses were performed according to the intention-to-treat method. The statistical package (RevMan and MetaView) provided by the Cochrane Collaboration was used. The methodological quality of the randomised clinical trials was evaluated by components of methodological quality. MAIN RESULTS: Combining the results of five randomised clinical trials randomising 499 patients with alcoholic hepatitis and/or cirrhosis demonstrated no significant effects of anabolic-androgenic steroids on mortality (relative risk (RR) 0.96, 95% confidence interval (CI) 0.72 to 1.28), liver related mortality (RR 0.83, 95% CI 0.60 to 1.15), complications of liver disease (RR 1.25, 95% CI 0.74 to 2.10), and liver histology. Further, anabolic-androgenic steroids did not significantly affect a number of other outcome measures. Anabolic-androgenic steroids were not associated with a significantly increased risk of non-serious adverse events but with the seldom occurrence of serious adverse events (RR 4.54, 95% CI 0.57 to 36.30). REVIEWER'S CONCLUSIONS: This systematic review could not demonstrate any significant beneficial effects of anabolic-androgenic steroids on any clinically important outcomes (mortality, liver related mortality, liver complications, and histology) of patients with alcoholic liver disease.
Anabolic Agents↗
Bile acids for viral hepatitis.
BACKGROUND: The viral hepatitides are common causes of liver diseases globally. Trials have assessed bile acids for patients with viral hepatitis, but no consensus was reached regarding their usefulness. OBJECTIVES: To assess the beneficial and harmful effects of bile acids for viral hepatitis. SEARCH STRATEGY: Searches were performed of the trial registers of The Cochrane Hepato-Biliary Group (September 2002), The Cochrane Library (Issue 2, 2002), MEDLINE (September 2002), EMBASE (September 2002), and The Chinese Biomedical Database (April 2001). SELECTION CRITERIA: Randomised clinical trials comparing any dose or duration of bile acids versus placebo or no intervention for viral hepatitis were included, irrespective of language, publication status, or blinding. DATA COLLECTION AND ANALYSIS: Two reviewers extracted the data independently. The methodological quality of the trials was evaluated with respect to generation of the allocation sequence, allocation concealment, double blinding, and follow-up. The outcomes were presented as relative risks (RR) or weighted mean differences (WMD) with 95% confidence intervals (CI). MAIN RESULTS: We identified 27 randomised trials of bile acids for hepatitis B or C; none were of high methodological quality. In one trial, ursodeoxycholic acid (UDCA) versus placebo for acute hepatitis B significantly reduced the risk of hepatitis B surface antigen positivity at the end of treatment and serum HBV DNA level at the end of follow-up. In another trial, UDCA versus no intervention for chronic hepatitis B significantly reduced the risk of having abnormal serum transaminase activities at the end of treatment. Twenty-five trials compared bile acids (21 trials UDCA; four trials tauro-UDCA) versus placebo or no intervention with or without co-interventions for chronic hepatitis C. Bile acids did not significantly reduce the risk of having detectable serum HCV RNA (RR 0.99, 95% CI 0.91 to 1.07), cirrhosis, or portal and periportal inflammation score at the end of treatment. Bile acids significantly decreased the risk of having abnormal serum alanine aminotransferase activity at the end of treatment (RR 0.82, 95% CI 0.76 to 0.90) and follow-up (RR 0.91, 95% CI 0.85 to 0.98). Bile acids significantly increased the Knodell score (WMD 0.20, 95% CI 0.08 to 0.31) at the end of treatment. No severe adverse events were reported. We did not identify trials including patients with hepatitis A, acute C, D, or E. REVIEWER'S CONCLUSIONS: Bile acids lead to a significant improvement in serum transaminase activities in hepatitis B and C. There is insufficient evidence either to support or to refute effects on viral markers, mortality, incidence of cirrhosis, or liver histology. Trials with high methodological quality are required.
Antiviral Agents↗
Bile acids for primary sclerosing cholangitis.
BACKGROUND: Bile acids have been used for treating primary sclerosing cholangitis, but their beneficial and harmful effects remain unclear. OBJECTIVES: To assess the beneficial and harmful effects of bile acids for patients with primary sclerosing cholangitis. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group's Trials Register, The Cochrane Library, MEDLINE, EMBASE, and The Chinese Biomedical Database generally from inception through to May 2002. SELECTION CRITERIA: Randomised clinical trials comparing any dose or duration of bile acids versus placebo, no intervention, or another intervention were included. Trials were included irrespective of blinding, language, or publication status. DATA COLLECTION AND ANALYSIS: Two reviewers extracted the data. The methodological quality of the trials was evaluated with respect to the generation of the allocation sequence, allocation concealment, double blinding, and follow-up. The results were reported by intention-to-treat analysis. The outcomes were presented as relative risks (RR) or weighted mean differences (WMD), both with 95% confidence intervals (CI). MAIN RESULTS: We identified six randomised clinical trials, all with low methodological quality. Patients were treated for three months to six years (median two years). Five trials (183 patients) compared ursodeoxycholic acid versus placebo, and one trial (40 patients) compared ursodeoxycholic acid versus no treatment. Ursodeoxycholic acid did not significantly reduce the risk of death (RR 0.86; 95% CI 0.27 to 2.73); treatment failure including liver transplantation, varices, ascites, and encephalopathy (RR 0.94; 95% CI 0.63 to 1.42); liver histological deterioration (RR 0.89; 95% CI 0.45 to 1.74); or liver cholangiographic deterioration (RR 0.43; 95% CI 0.18 to 1.02). Ursodeoxycholic acid significantly improved serum bilirubin (WMD -14.6 micro mol/litre; 95% CI -18.7 to -10.6), alkaline phosphatases (WMD -506 IU/litre; 95% CI -583 to -430), aspartate aminotransferase (WMD -46 IU/litre; 95% CI -77 to -16), and gamma-glutamyltranspeptidase (WMD -260 IU/litre; 95% CI -315 to -205), but not albumin (WMD -0.20 g/litre; 95% CI -1.91 to 1.50). Ursodeoxycholic acid was well tolerated. REVIEWER'S CONCLUSIONS: Ursodeoxycholic acid leads to a significant improvement in liver biochemistry, but there is insufficient evidence to either support or refute its clinical effects in patients with primary sclerosing cholangitis. Large scale, high-quality randomised clinical trials are needed.
Cholagogues and Choleretics↗
Sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone for HBeAg-positive chronic hepatitis B.
BACKGROUND: Chronic hepatitis B has serious effects on morbidity and mortality. Alfa interferon has been shown to increase the rates of HBeAg-clearance as well as seroconversion to anti-HBe, but response rates are unsatisfactory. Glucocorticosteroid pretreatment may increase the response to alfa interferon. OBJECTIVES: The objectives were to assess the effects of the sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone in hepatitis B 'e' antigen positive chronic hepatitis B on mortality, virological response, biochemical response, liver histology, quality of life, and adverse events. SEARCH STRATEGY: Electronic searches of the controlled trial registers of The Cochrane Hepato-Biliary Group and The Cochrane Library, MEDLINE, BIOSIS, and EMBASE were combined (May 2000). Reading the bibliography of retrieved articles identified further trials. Alfa interferon-manufacturing companies were approached in order to inquire about any published and unpublished randomised trials. SELECTION CRITERIA: The analyses included randomised trials comparing identical alfa interferon treatment regimens with and without glucocorticosteroid pretreatment for hepatitis B 'e' antigen positive chronic hepatitis. The trials could be open, single blinded, or double blinded. No patient exclusion criteria were applied. DATA COLLECTION AND ANALYSIS: Three reviewers independently selected the trials and one extracted the data, which were validated. Assessments of the outcome measures were performed at the end of treatment and at six months and at maximal follow up after the end of treatment with alfa interferon. MAIN RESULTS: A total of 13 randomised trials including 790 patients were included. Loss of hepatitis B 'e' antigen (OR 1.41, 95% confidence interval 1.03 to 1.92, P = 0.03) and hepatitis B virus DNA (OR = 1.51, 95% confidence interval 1.12 to 2.05, P = 0.008) were significantly more frequent among patients treated with the sequential combination of glucocorticosteroids and alfa interferon than among patients treated with alfa interferon alone. Glucocorticosteroid pretreatment did not significantly influence seroconversion from hepatitis B 'e' antigen to antibodies to hepatitis B 'e' antigen, loss of hepatitis B surface antigen, normalisation of alanine aminotransferase/aspartate aminotransferase activities, and severity of adverse events. Glucocorticosteroid pretreatment did not significantly affect mortality and adverse events. The effect of glucocorticosteroid pretreatment on liver histology and quality of life could not be assessed due to insufficient data. REVIEWER'S CONCLUSIONS: Pretreatment with glucocorticosteroids before treatment with alfa interferon in patients with hepatitis B 'e' antigen positive chronic hepatitis B may be more effective than treatment with alfa interferon alone with regard to loss of hepatitis B 'e' antigen and hepatitis B virus DNA, but evidence for effect on clinical outcomes is lacking.
Antiviral Agents↗
Ursodeoxycholic acid for primary biliary cirrhosis.
BACKGROUND: Primary biliary cirrhosis is a rare autoimmune liver disease and an effective treatment has been difficult to establish. Some randomised clinical trials have found an effect of ursodeoxycholic acid for primary biliary cirrhosis. OBJECTIVES: Evaluate the beneficial effects and adverse effects of peroral ursodeoxycholic acid for primary biliary cirrhosis versus placebo or no intervention. SEARCH STRATEGY: The Controlled Trials Register of The Cochrane Hepato-Biliary Group, The Cochrane Library, MEDLINE, EMBASE and the full text of the identified studies were searched until April 2001. The electronic searches were done by entering the search terms 'ursodeoxycholic acid', 'UDCA', 'primary biliary cirrhosis', and 'PBC'. SELECTION CRITERIA: Randomised clinical trials evaluating ursodeoxycholic acid administered perorally at any dose versus placebo or no intervention in patients with primary biliary cirrhosis diagnosed by any method. Only trials using an adequate method for randomisation were included, regardless of blinding and language. DATA COLLECTION AND ANALYSIS: The methodologic quality of the randomised clinical trials was evaluated by components and the Jadad-score. The following outcomes were extracted: mortality, liver transplantation, pruritus, other clinical symptoms (jaundice, portal pressure, (bleeding) oesophageal varices, ascites, hepatic encephalopathy, hepato-renal syndrome, autoimmune conditions), liver biochemistry, liver function, liver biopsy findings, quality of life, and adverse events. All analyses were performed according to the intention-to-treat method. MAIN RESULTS: A total of 16 randomised clinical trials evaluating ursodeoxycholic acid against placebo (n = 15) or no intervention (n = 1) in 1422 patients were identified. The median Jadad-score was 3 (range 1-5). A number of trials described as double blind had problems with the blinding. Neither mortality (odds ratio = 0.94; 95% confidence interval (CI) 0.60 to 1.48), liver transplantation (odds ratio = 0.83; 95% CI 0.52 to 1.32), mortality or liver transplantation (odds ratio = 0.90; 95% CI 0.65 to 1.26), pruritus, fatigue, autoimmune conditions, quality of life, liver histology, or portal pressure were significantly affected by ursodeoxycholic acid (given in doses of 8-15 mg/kg/day for three months to five years). However, ursodeoxycholic acid significantly (P < 0.05) reduced ascites, jaundice, and biochemical variables such as serum bilirubin and liver enzymes. Ursodeoxycholic acid was not significantly associated with adverse events. Including data after patients had been switched onto open label ursodeoxycholic acid confirmed the findings regarding the lack of a significant effect of ursodeoxycholic acid on mortality and mortality or liver transplantation. A significant (P = 0.04) effect was, however, observed on the incidence of liver transplantation (odds ratio = 0.68; 95% CI 0.48 to 0.98). REVIEWER'S CONCLUSIONS: Ursodeoxycholic acid has a marginal therapeutic effect for primary biliary cirrhosis. On the positive side, ursodeoxycholic acid has few side effects. The general usage of ursodeoxycholic acid for primary biliary cirrhosis needs reevaluation.
Administration, Oral↗
Ribavirin with or without alpha interferon versus no intervention, placebo or alpha interferon for chronic hepatitis C.
BACKGROUND: Hepatitis C is a major cause of liver-related morbidity and mortality. Ribavirin plus interferon combination therapy is presently considered the optimal treatment of interferon naive patients with chronic hepatitis C, but its role in relapsers and non-responders to previous interferon therapy is not established. OBJECTIVES: To assess the efficacy and safety of ribavirin alone or in combination with alpha interferon in interferon naive patients, relapsers, and non-responders with chronic hepatitis C. SEARCH STRATEGY: Eligible trials were identified through electronic databases, manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies producing ribavirin or interferon (August 2001). SELECTION CRITERIA: We included all randomised trials comparing ribavirin with or without alpha interferon versus no intervention, placebo, or alpha interferon for chronic hepatitis C. DATA COLLECTION AND ANALYSIS: The primary outcome measures were the 'sustained' (six months after treatment) virological response, and morbidity plus mortality. The secondary outcome measures were the 'end of treatment' and 'sustained' biochemical response, the 'end of treatment' virologic response, histology, quality of life, and adverse events. MAIN RESULTS: We included eight trials in which 271 patients were randomised to ribavirin versus placebo or no intervention and 48 trials in which 6585 patients were randomised to interferon with or without ribavirin. Compared with placebo or no intervention, ribavirin monotherapy had no significant effect on the virological response or histology and only a transient effect on the biochemical response. Compared with interferon, combination therapy reduced the risk of not having a sustained virological response by 26% in naive patients (relative risk (RR) 0.74; 95% confidence interval (CI) 0.70-0.78), 33% in relapsers (RR 0.67; 95% CI 0.57-0.78), and 11% in non-responders (RR 0.89; 95% CI 0.83-0.96). There was no significant effect on morbidity plus mortality (Peto odds ratio 0.45; 95% CI 0.19-1.06). Irrespective of previous therapy, combination therapy significantly reduced the risk of not having a sustained biochemical response (RR 0.76; 95% CI 0.59-0.84) or improved histology (RR 0.67; 95% CI 0.56-0.81). Combination therapy also significantly increased the risk of treatment discontinuation (RR 1.28; 95% CI 1.07-1.52) and several types of adverse events. REVIEWER'S CONCLUSIONS: Combination therapy increased the number of naive patients, relapsers, and non-responders with a sustained virological, biochemical, or histological response, but also the occurrence of adverse events.
Antiviral Agents↗
Propylthiouracil for alcoholic liver disease.
BACKGROUND: Alcohol is the most common cause of liver disease in the Western world today. Randomised clinical trials have addressed the question whether propylthiouracil has any efficacy in patients with alcoholic liver disease. OBJECTIVES: The objectives were to assess the efficacy of propylthiouracil on mortality, clinical symptoms and complications, liver biochemistry, and liver histology in patients with alcoholic liver disease. Adverse events were also analysed. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register (searched July 2001), The Cochrane Controlled Trials Register (Cochrane Library Issue 3, 2001), MEDLINE (January 1966 to July 2001), EMBASE (January 1985 to July 2001) were searched. These electronic searches were combined with full text searches. Manufacturers and researchers in the field were also contacted. SELECTION CRITERIA: Randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included. Interventions encompassed propylthiouracil at any dose versus placebo or no intervention. The trials could be double-blind, single-blind, or unblinded. The trials could be unpublished or published as an article, an abstract, or a letter and no language limitations were applied. DATA COLLECTION AND ANALYSIS: All analyses were performed according to the intention-to-treat method. The statistical package (RevMan and MetaView) provided by the Cochrane Collaboration was used. The methodological quality of the randomised clinical trials was evaluated by components of quality and the Jadad-scale. MAIN RESULTS: Combining the results of six randomised clinical trials including 710 patients demonstrated no significant effects of propylthiouracil versus placebo on mortality (Peto odds ratio (OR) 0.91, 95% confidence interval (CI) 0.59 to 1.40), liver related mortality (OR 0.78, 95% CI 0.45 to 1.33), complications of the liver disease (OR 1.14, 95% CI 0.58 to 2.24), or liver histology. Propylthiouracil was associated with a non significant trend towards an increased risk of non-serious adverse events (OR 1.49, 95% CI 0.74 to 2.99) and with the seldom occurrence of serious adverse events (leukopenia). REVIEWER'S CONCLUSIONS: This systematic review could not demonstrate any significant efficacy of propylthiouracil on any clinically important outcomes (mortality, liver related mortality, liver complications, and liver histology) of patients with alcoholic liver disease and propylthiouracil was associated with adverse events. Accordingly, there is no evidence for using propylthiouracil for alcoholic liver disease outside randomised clinical trials.
Antimetabolites↗